Certain bis-dioxopiperazines of formula (I) are cytotoxic and have been used in the treatment of cancer. Thus UK patent 1,234,935 describes the compounds of formula (I) having R=CH.sub.3 and R'=R"=H (as the dl, d and l isomers); R=R'=R"=H; R=R'=CH.sub.3 and R"=H (as the meso isomer); and R+R'=--CH.sub.2 CH.sub.2 -- and R"=H. Of these the first named compound has proved to be of most value although a further compound of formula (I) having R=R'=H and ##STR2## has also been used in treating cancer. ##STR3##
In UK Patent 2,173,195 pro-drugs of bis-dioxopiperazines of formula (I) such as those of UK Patent 1,234,935 are described. In the case of these pro-drugs the activity is indicated as extending to cardioprotection in addition to the treatment of cancer.
Studies have been reported by various authors on the chelating properties of these bis-dioxopiperazines and the use in treatment of lead poisoning has been proposed by Wittig and Hultsch, Int. Arch. Occup. Environ. Health, 1981, 48, 89, for the compound of formula (I) having R=R'=H and R"=CH.sub.3 and by May et al, Agents and Actions, 1984, 15, 448 and Willes and Williams, Plzen. Lek. Sborn., 1985, 49, 113, for the compound having R=R"=H and R'=C.sub.2 H.sub.5 in the dl form.
German Offenlegungschrift 2,511,891 describes the use of certain bis-dioxopiperazines of formula (I) for the treatment and prophylaxis of thrombosis and embolism. These compounds (I) include, inter alia, those in which R and R' are linked so as to form a cycloalkyl residue of unspecified size and R" is C.sub.1-6 alkyl, with the sum of the carbon atoms in R, R' and R" being greater than two.
In Research Communications in Chemical Pathology and Pharmacology, 1985, 48, 39, Herman et al report tests on the protective effect against acute daunorubicin toxicity of a range of bis-dioxopiperazines of formula (I). They conclude that although the compound bimolane ##STR4## and the compound having R=CH.sub.3 and R'=R"=H (as the dl, d or l isomer) give protection against the lethal effects of daunorubicin, the remainder of the compounds tested (R=R'=R"=H; R=R'=H and R"=CH.sub.3 ; R=R"=CH.sub.3 and R'=H (l); R=R'=CH.sub.3 and R"=H (meso); R=C.sub.2 H.sub.5 and R'=R"=H (dl); R: CH.sub.3, R'=C.sub.2 H.sub.5 and R"=H (dl-erythro); and R+R'=--CH.sub.2 --CH.sub.2 -- and R"=H; as well as the compound in which --CHR--CHR'-- is replaced by --(CH.sub.2).sub.3 -- and the ring opened bis-diacid diamide compound having R=CH.sub.3 and R'=H) all showed either no protective activity or only minimal protective activity.
Despite the indications to the contrary in this Herman et al paper to the effect that of the bis-dioxopiperazine drugs only bimolane and the compound having R=CH.sub.3 and R'=R"=H are of value as cardioprotective agents, we have now found that certain other bis-dioxopiperazine drugs may with advantage be used as protective agents, in particular as cardioprotective agents. These bis-dioxopiperazines are of especial interest for providing protection against the cardiotoxic effects of various anthracycline drugs and in particular of doxorubicin (adriamycin). In this context it is relevant that, in addition to the comments in the Herman et al Research Communications in Chemical Pathology and Pharmacology paper, it is indicated by Herman et al in Advances in Pharmacology and Chemotherapy, 1982, 19, 249 that even the cardioprotective compound ICRF 159, which is the dl isomer of the compound of formula (I) having R=CH.sub.3 and R=R'=H, is consistently more effective in reducing high dose daunorubicin toxicity than doxorubicin toxicity.